Osteoarthritis is one of the most common diseases suffered by elderly persons in Western countries. This disabling joint disorder is usually multifactorial in nature and thus of unknown origin in individual cases. During the early stages of osteoarthritis, localized lesioning of the articular cartilage layer is a characteristic occurrence. Once initiated, this lesioning process is progressive, and no prophylactic measures are available to arrest it. Likewise, no established biologically-based treatment strategies are available to induce the healing of these structural defects. Endeavours are now being made to adopt a more biologically rational approach to the repair of articular cartilage lesions using tissue-engineering principles. We have recently developed a growth-factor-based strategy which induces the healing of small articular cartilage defects. But when applied to very large defects in experimental animals (goats), the same strategy is unable to induce their repair within a short period of time. - We postulate that by introducing an adult stem cell population directly into the defect space by the autotransplantation of synovial membrane flaps, the difficulties can be overcome and the repair of large defect areas and volumes induced. We hypothesize that a "layered synovioplasty" performed in a single intervention (surgery or arthroscopy) can form the basis for the repair of bulk volume articular cartilage defects. Layers of synovial flaps will be interposed with a matrix containing growth factors in a controlled release system, which will assure their transformation. - We will first optimize the transformation conditions using a tissue-culture system based on the availability of fresh synovial bovine tissue (from young adult cows). - We also hypothesize that adult stem cell populations within different synovial joints of the body contain positional information respecting their differentiation potential into joint- specific articular cartilage. This being the case, the local recruitment of adult synovial stem cells would be a great advantage, in that the cells would carry local positional information to form the same type of joint-specific articular cartilage. We will test this hypothesis using articular cartilage tissue as well as synovial tissue from three different bovine joints that differ significantly both structurally and functionally, i.e., from the shoulder joint, from the knee joint and from the metatarsal joint of bovine origin. - Following fine-tuning, the optimized protocols will be cross- checked in vitro using adult goat material derived from the knee joint. The finalized protocols will be tested at mid- term (5 weeks post-operatively) and long-term (6 months post-operatively) junctures in adult goats. The repair tissue will be analyzed quantitatively with respect to mRNA expression profiles and the post-translational expression of cartilage matrix components, as well as morphometrically, ultrastructurally and biomechanically. We believe that this project is highly innovative and that the results of this research will have a significant impact on the future treatment of osteoarthritic lesions and on improvement of the health status of the US population. [unreadable] [unreadable] [unreadable]